Fertility Options for Single Women

Single women may face some challenges regarding fertility options: understanding them then picking one or more options, suitable for your reproductive plans. Clearly, a woman cannot delay pregnancy indefinitely, as the number of good quality eggs decline quickly in her 30s and older.

Decline in Fertility with age

Modern reproductive medicine enables single women to be mothers now and in the future. As with anything in reproduction, the younger you are, the more successful your efforts will ultimately be, irrespective of your choices. In addition, think of what would you accept: donor sperm? are you ready to get pregnant now or do you want do that in the future?

Are you ready to Start a Family without a Partner?

This could be a difficult question considering the time, financial and emotional commitment of raising children without a male partner. A psychologist with expertise in reproductive issues can help women tackle issues as readiness and commitment, disclosure to children when mature, capitalizing on family resources, legal issues and many more. Some anonymous donors accept open identity in the future.

Starting a family without a male partner requires a selection of sperm donor. The sperm donor could be anonymous (from a sperm bank) or known (friend). In either cases, the donor is screened for infectious diseases (hepatitis B, hepatitis C, HIV, Syphilis, Gonorrhea and Chlamydia) and common genetic abnormalities. The sperm is quarantined then the donor is retested for infectious diseases. Tests are done in a specialized high accuracy labs.

How to use donor sperm to achieve a pregnancy?

This is a question related to female ovarian reserve and other fertility factors. If the fallopian tubes are open, as indicated by HSG (hysterosalpingogram, X-ray of the tubes) then IUI (intrauterine insemination) is possible. Age is also an important factor. Women 38 or older have much higher chance of conceiving with IVF than IUI using frozen sperm. This issue require thorough evaluation by a reproductive endocrinologist.

On Starting a Family with a Partner in the Future

If the use of donor sperm is not acceptable, egg freezing is a viable option for women with reasonable ovarian reserve and younger than 40. Evaluation of antral follicle count using vaginal ultrasound and antimullerian hormone levels (AMH) can predict response to fertility medications and ultimate egg yield from the cycle. Age reflects well how many of these eggs are chromosomally normal. The ovaries are stimulated using injection medications. Eggs are retrieved under vaginal ultrasound guidance which is a minor procedure. Mature eggs are frozen 4 hours later using vitrification. Immature eggs are cultured for <24 hours and frozen if mature. The eggs can be stored for years to come.

If the number of eggs retrieved is low another egg freezing cycle can be attempted to freeze more eggs.

When pregnancy is desired the eggs are thawed and fertilized via ICSI (direct injection of the sperm into the egg) and the resulting embryos are transferred into the uterus after preparation of its lining. The pregnancy rate after egg freezing is close to fresh eggs and is age dependent.

These options allow single women achieve their reproductive goals while respecting their values and preferences.

Fertility Treatment: Do not be Distracted

When contemplating options for fertility treatment with your own eggs, it always boils down to continue frequent intercourse, ovarian stimulation / ovulation induction + IUI or some form of IVF. During consultation or when weighing your options do not lose perspective of the big picture. Many suggestions may present themselves and serve to distract you. Men and Women load up on these distractions from the web, friends, primary care physicians or the couple themselves. Some of these recommendations are harmful because they shift the focus to non-proven interventions and most notably cause delay consultations with a reproductive endocrinologist and completing the infertility workup or starting treatment if needed.

Do not be distracted by these arguments

I am Healthy

Many women in America consider being healthy as being fertile. The media also bombard us with photos of beautiful women in their forties with babies. Truly many women, are in great shape with ideal body weight, exercise regularly, have no medical problems and feel great about themselves.

Fertility though speaks to a specific set of factors related to the ovaries, fallopian tubes and quality of sperm. Healthy women can have low egg reserve or blocked fallopian tubes or their partners have low sperm counts. Hence their fertility could be impaired. On the other hand, women not leading a healthy lifestyle or having a medical disorder can be very fertile if all fertility factors (tube, ovary, sperm) are functional.

I did not try enough

If you do not use birth control pills or condoms and you have having regular intercourse, then you are trying, irrespective of your conscious intentions. If you are you had regular intercourse for one year and are younger than 35 years or six months and 35 or older, then you have tried. Regular intercourse means two to three times a week. If you had intercourse with reasonable frequency for 6months to a year and you are not pregnant consult with a fertility specialist. There is a strong relationship between the length of trying and pregnancy rate. The longer that you have been trying, the lower the chance for spontaneous conception.

I did not time my ovulation

Timing your ovulation is not required at all if you are trying to conceive. Actually timing your ovulation maybe harmful to your chance to conceive. Because the methods you would use to time ovulation (cervical mucus, ovulation prediction kits, basal body temperature or intelligent thermometers and apps) are not accurate, you may miss valuable time and have intercourse at the wrong time if ovulation takes place unexpectedly early. Moreover, you cannot get higher odds for getting pregnant above and beyond having intercourse three times a week because sperm will be available all the time when you ovulate. Several studies failed to show any increase in pregnancy rates using many of these timing methods.

My progesterone level is not optimal

For almost all women, low progesterone level is not a cause for infertility. In natural cycles, progesterone starts to rise after ovulation. Levels of 3 nanogram/mL or more indicates ovulation, Optimal levels to maintain the lining of the uterus are 8 to 10ng/mL. Levels less than 8 (luteal phase defect) may lead to miscarriage because progesterone is not adequate to maintain the lining of the uterus but it is not a cause for not getting pregnant (infertility). Progesterone is monitored, and supplemented if low, during fertility treatment but in itself low progesterone is not a cause for infertility.

On Clomid & Letrozole

Clomiphene is widely used as initial fertility treatment. This use is commonly not appropriate because

b. clomid is used without performing basic tests related to the safety of getting pregnant (infectious disease and genetic screening)

c. clomid is used by women that are not likely to benefit from it e.g regularly ovulating women with low ovarian reserve and unexplained infertility. Women that are most likely to benefit from clomid are women with chronic anovulation e.g women with polycystic ovary syndrome (PCOS).

d. clomid is commonly used with no monitoring using ultrasound. If you do not get pregnant, one would not know if you did ovulate or not. 10-20% of women do not respond to clomid. If you are destined to get pregnant, there is a possibility that you have many eggs developing in the ovary because you are unduly sensitive to the medicine. Strong response to clomid makes you at risk for multiple pregnancy

e. clomid is commonly use for extended periods of time while the majority of pregnancies take place in the first 3 months.

f. IUI is preferred to intercourse only, in clomid cycles because it can cause the cervical mucus to be thick. IUI bypasses the cervical mucus and deposit the sperm into the cavity of the uterus

g. Letrozole is similar to clomid regarding the use and indication but there is evidence that pregnancy is higher after letrozole compared to clomid.

Use clomid or better ltrozole for the right indication, with monitoring and for 3 (max 6) months only.

On Setting Time Limits

For each fertility treatment step: intercourse, ovarian stimulation + IUI or IVF define the number of cycles you will try before proceeding to the next step. Statistically, these treatments are more likely to succeed in the first three treatment attempts. Subsequently, the chance for getting pregnant diminishes and you and your physician should consider moving to another treatment.

Do not loose track of your age and ovarian reserve

You have normal fallopian tubes and partner sperm and you ovulate every month. Younger women are encouraged to try (have regular intercourse). The duration of trying on your own should be guided by ovarian reserve tests and age. Younger women with good reserve can try a bit longer than older women or women with low reserve. This recommendation should be based on scientific information not general perception. Do not accept the advice ‘ keep trying’ from any one without considering you age and without performing the tests for ovarian reserve (vaginal ultrasound, AMH and FSH on day 3). Female age is the most important factor in occurrence of a healthy pregnancy and should be the prime consideration even if ovarian reserve tests and other factors are normal.

There is a plethora of low quality information, recommendation and advice out there. Women accumulate them from multiple sources or just using there simple logic. They can lead to delay in fertility testing and fertility treatment that could be detrimental to future fertility.

Pre-implantation Genetic Screening (PGS): What are we really talking about?

The tenant behind pre-implantation genetic screening (PGS) is to biopsy one or few cells from each embryo after creation, analyze the chromosomes for each embryo and transfer the ones that has normal chromosomes back into the uterus to boost IVF success and increase the live birth rate.

Central to this idea is that abnormal chromosomes in the embryos is the main reason why an embryo does not yield a newborn. It is logic then that PGS should allow the selection for the best embryo (preferably one only) for transfer into the uterus ending into one singleton newborn.

If this premise is accepted then the following assumptions should also be generally accepted

a. All or the majority of embryos reached the appropriate stage of development and expansion to allow biopsy.

b. Biopsy of the embryo does not harm its ability to implant

c. The cell or few cells obtained represent the rest of the embryo (has identical chromosomes to all the other cells in the embryo)

d. The platform used to analyze the embryo chromosomes is close to 100% accurate (otherwise some embryos will be wasted because they are abnormal according to the test, while they are actually normal). The platform reports only the chromosomes of the embryo and is not accountable for other elements of implantation i.e. the endometrium.

e. The delay (one or more days) needed to finish the testing does not affect embryo implantation

f. Freezing and then thawing of a biopsied embryo does not affect its implantation potential

g. Patients and physicians have agreed on how to calculate success: how many live births one would obtain from all embryos resulting from a single IVF cycle (all fresh and frozen embryos) i.e. total potential of one IVF cycle versus fresh embryo transfer only.

h. The added cost of biopsy and testing of embryos, potential increases the delivery rate and reduces the incidence of multiple pregnancy and miscarriage is cost-effective from the viewpoint of individual and a modern society.

The initial attempt to perform Preimplantation genetic diagnosis using an old technology called FISH that tested 7 to 9 chromosomes proved harmful few years ago and that its wide adoption at that time was a form of medical illiteracy : because it depends on logic not actual well conducted study. When the studies were conducted, they all showed that women universally achieved lower pregnancy rates after PGS.

New platforms are now available to test for all the chromosomes (array cGH and SNP array) and using cells (trophoectoderm) obtained from more advanced stages of the embryo (blastocyst). The question in hand is should we adopt these techniques, not as a research tool, but as the standard of care that should be offered to the majority of women undergoing IVF?

How Effective is PGS? The case for Logic

a. Not all embryos will reach the blastocyst stage (day 5) to be suitable for biopsy. Not all physicians and patients push their embryos to the blastocyst stage especially if few embryos exist in culture on day 3. Moreover, some normal embryos may not survive extended culture to blastocyst.

b. There are no conclusive evidence that biopsy of the trophoectoderm (the part that makes the placenta) of an embryo does not harm the embryo.

c. Mosaicism ; when one or few cells are different in chromosomes than the rest of the cells, is known to take place in embryos. The cells in the trophoectoderm maybe abnormal while the cells in the embryo maybe normal. Interestingly the embryo can later get rid of the abnormal cells in the trophoectoderm. This can lead in misdiagnosis of the embryo as abnormal while the embryo itself has the potential to implant and yield a healthy baby.

d. The platform used to analyze the embryo chromosomes is not 100% accurate either because of the accuracy of the test itself or because of mosaicism. The accuracy reported by labs administering the test is 97%. This means some normal embryos will be discarded and some abnormal embryos will be transferred. Actually the accuracy was not validated by many labs, only very few worldwide. Clinically some physicians have experienced much lower accuracy (80 or 90%). The platform reports only the chromosomes of the embryo and is not accountable for other elements of implantation i.e. the endometrium. So it is possible that the lower accuracy is due to other elements on embryo gentics (other than the number of chromosomes) or the lining of the uterus.

e. Currently the transfer of embryos into the uterus has to be delayed for one day (day 6) or several weeks (embryo has to be frozen then thawed back after results are obtained). This delay may reduce implantation of the embryo because it will not match the window of implantation in the lining of the uterus. This is a controversial point as some researchers found no difference in implantation between day 5 and day 6. This research, however, is not widely replicated.

f. After PGS some ‘normal’ embryos will be frozen. The survival of thawed and biopsied embryos is maybe reduced, potentially leading to loss of normal embryos. No large studies on survival of biopsied embryos after thaw exist.

g. Patients and physicians have agreed on how to calculate success: if success is calculated based on how many live births one would obtain from all embryos resulting from a single IVF cycle (fresh and frozen) i.e. total potential of one IVF cycle, then PGD has no value as it will not make an abnormal embryo normal or vice versa. If the success is based on what happens in the fresh cycle only with no regard to frozen embryos then PGS may improve the success rate of IVF. All assuming an excellent embryo freezing program.

For exampe If you are a young woman <38, with a good number of available embryo on day 5, say 4 blastocysts that are suitable for biopsy, you may elect to

i. transfer one embryo in the fresh cycle and freeze 3 embryos. If you are not pregnant, then transfer one embryo in each subsequent frozen cycle. If you are destined to get pregnant you will do that within a maximum of 3 months after your initial IVF and the risk for multiple pregnancy is minimized to 1% or less. If you were not destined to get pregnant no testing would have helped you or

ii. Alternatively, you may elect to test all your embryos in the fresh cycle, transfer one normal embryo, if any and freeze any normal embryo remaining. The potential benefit is getting pregnant in the fresh cycle instead of getting pregnant 1-3 months later. Also you will reduce the risk of miscarriage because abnormal embryos will likely be eliminated. The potential risks are misdiagnosis by PGS (not 100% accurate), loss of a thawed embryo (did not survive biopsy and freeze) and lower implantation potential of a normal embryo due to biopsy and delayed transfer.

h. A cost-effective analysis for PGS is not available at this time. The added costs are biopsy and testing of embryos. The potential benefits are increase in the delivery rate and reduction in multiple pregnancy and miscarriage. In the scenario above you either pay for i. frozen embryo transfer(s) if you do not get pregnant in the fresh cycle or ii. pay for ICSI (required for PGS by the majority of programs), biopsy and testing in the fresh cycle and frozen embryo transfer(s) if you do not get pregnant in the fresh cycle. In terms of multiple pregnancy, it can be minimized in either pathways if your physician is transfers one embryo anyway, tested or not. Things are not that simple, the payer will also make a difference: PGS is completely out of a patient pocket as it is not covered by any insurance while frozen embryo transfer may or may not be covered.

How Effective is PGS? The case for Published Studies

In general decision making in biological sciences is not amenable to logic, but determined by well designed ad well conducted studies. So far, three studies were published using the new platforms for embryo chromosome analysis, aiming at increasing IVF success. The studies were criticized because of

1. Restricted to young women (median age 31 to 32) so results cannot be generalized to the general IVF population: 2 studies

2. Did not account for frozen embryos: all studies

3. The studies did not demonstrate superiority of PGS to transfer best embryos based on morphology (shape): one study. Specifically a transfer of a tested embryo in the fresh cycle was not inferior to transfer of two untested embryos. Non inferiority does not mean superiority. Noninferiority study design is not suitable for a PGS study as patients and physicians are only interested in such an expensive treatment that can harm their embryos only if it promises superior results for their infertility treatment. Moreover, treatment could actually be inferior because a limit is placed that will make the outcome non inferior, in that study 20%. So if the difference is less than 20% PGS is considered not inferior.

4. End point should be live birth or ongoing pregnancy. Surrogate or intermediate endpoints as pregnancy, implantation (short of a baby in hand or at least pregnancy beyond 20 weeks) are not ideal outcomes.

Randomized studies related to pre-implantation genetic testing using newer platforms were independently analyzed. So far no study showed that PGS is superior to the strategy of transferring the best embryo based on morphology (the standard of care). Moreover due to factors related to the biology of reproduction and that the accuracy of the test is unlikely to reach 100% accuracy soon, it is unlikely that PGS will prove beneficial to women undergoing IVF for fertility treatment. PGS may only shorten the time to pregnancy but will not be able to improve the pregnancy rate and due to inaccuracies may even reduce it.

Alternatives to PGS are being studied. One alternative is time lapse photography of the embryos to observe the cell division of the embryo cells and select the best embryo for transfer. It is noninvasive but further studies are required before its ready for general use. Another alternative is polar body biopsy of oocytes but results of ongoing studies are not available yet.

It is possible that factors in this article could be interpreted differently in a specific situation by patients and their physicians, in conjunction with the number of mature eggs produced, but it does not appear that PGS is ready for generalized application in the majority of IVF population.

Following detailed fertility investigation of the male tubal and ovarian factors, patient and her reproductive endocrinologist decide together on the optimal fertility treatment options.

Factors to consider in selecting the best fertility treatment options include:

Sperm source

Is there a male partner: if so what is the ejaculate volume, sperm concentration, motility and shape? if >10 million moving sperm then pregnancy through intercourse or IUI is possible. Lower numbers indicates IVF or ICSI. If azospermia (no sperm in the ejaculate) then surgical sperm retrieval may be needed (TESE) or donor sperm can be used.

Blocked and dilated fallopian tubes (Hydrosalpinx) require surgical removal of the dilated tubes followed by IVF. Dilated tubes are very difficult to fix and can leak fluid into the uterine cavity and prevent implantation of the embryo.

Ovarian Factor

Women who do not ovulate due to polycystic ovary syndrome (PCOS): ovulation can be induced using oral medications (clomid or letrozole) or injection medications (gonadotropins). This is usually combined with IUI.

Women who do not ovulate due to defect in the master gland in the brain (Hypothalamic amenorrhea): ovulation can be induced using injection medications (gonadotropins). This is usually combined with IUI.

Women diminished ovarian reserve and unexplained (idiopathic) infertility commonly have lower quality eggs and may benefit from inducing multiple ovulation followed by IUI or IVF, to increase the chance that one of the eggs is healthy (chromosomally normal).

Donor Eggs

Donor eggs are needed in women with low egg reserve that fail multiple IVF cycles after menopause or those who carry some genetic abnormalities.

Donor eggs can enable same sex male couples parent a child (together with a gestational carrier).

Gestational carriers

Gestational carriers enable women to parent a child if the uterus is absent or was removed due to a disease e.g endometrial cancer or if the lining of the uterus is damaged e.g intrauterine scarring due to prior scrapping.

Gestational carrier enable women who cannot get pregnant to parent a child e.g history of breast cancer

Gestational carriers enable same sex male couples to parent a child.

Genetic analysis of the eggs or embryos (PGD)

Women and men with risk of conceiving a child with a specific genetic disorder e.g cystic fibrosis, sickle cell anemia should consider testing their embryos before transfer into the uterus (PGD)

PGD can also be used for selecting the sex of the baby for family balancing.

PGD can be used to test the chromosomes of the embryo to increase the chance for pregnancy in women select women but its efficacy for that purpose is still being investigated.

Fertility Preservation

Women at risk for diminished fertility due to a medical problem or treatment e.g breast cancer can freeze their eggs or embryos to use later

Men at risk for azospermia due to genetic factors, cancer and cancer treatment can freeze sperm for use later

Many other techniques for fertility preservation can also be applied to adults and children to preserve reproductive organs and tissue.

Some women encounter thin endometrial lining and abnormal pattern during natural cycles or during fertility treatment. The implantation of embryos is impaired in women with thin lining and abnormal pattern. Abnormal lining can lead to recurrent implantation failure in young women undergoing IVF after repeated transfer of good quality embryos.

The thickness of the lining appropriate for implantation is commonly defined at 7 to 13mm measured on vaginal ultrasound. The most receptive pattern of the lining of the uterus is a tri-laminar pattern (three line pattern) without little homogenous pattern when visualized shortly before ovulation (pattern 1 and 2 of the photo, Fanchin et al 2000).

Causes for Abnormal Endometrial lining during Fertility Treatment

The two most common abnormalities encountered are

a. Fluid inside the Cavity: fluid may accumulate inside the cavity due to stenosis (narrowing) of the cervix probably because of prior surgery or leak of fluid from a blocked dilted fallopian tube (hydrosalpinx).

1. Acquired (Asherman Syndrome): prior D&C (termination of pregnancy), uterin surgery (e.g fibroid surgery) or tuberculosis in women from certain geographical locales. All work through the formation of scar tissue inside the uterus.

2. Idiopathic: no prior cause is identified.

Evaluation of The Uterine Cavity

Proper evaluation of the uterine cavity and lining is an integral component of fertility evaluation and monitoring is also essential during treatment. Methods of evaluation include

i. Vaginal ultrasound for the thickness and pattern during the follicular and luteal phases of the menstrual cycle

ii. Evaluation of the cavity of the uterus using HSG (hysterosalpingogram), saline sonography (water sonogram) or hysteroscopy. Saline sonography is the most invasive and is a very accurate method for evaluation of the cavity and identify if a lesion arising from the wall of the uterus projects into the cavity.

iii. Endometrial biopsy: rarely indicated. The lining of the uterus is sampled and with special stain to detect chronic infection. The value of this testis questionable.

Treatment of Abnormal Endometrial Lining

Many treatments are available to normalize the cavity of the uterus and improve the lining

1. Excision of hydrosalpinx: a dilated blocked fallopian tube especially those seen on ultrasound should be excised to avoid leak of fluid into the uterus. This has the potential of doubling the implantation rate of embryos. Laparoscopy can be used to remove dilated tubes in a minimal access day surery

2. Asherman syndrome: operative hysteroscope can be used to accurately cut the scar tissue and allow the surrounding healthy lining to cove the row area. The lining is treated with estrogen after surgery to promote healing

3. Uterine fibroids and polyps and spetum can be removed using operative hysteroscope.

4. Antibioitics to treat chronic inflammation of the lining of the uterus are seldom effective.

5. During IVF if the lining is not favorable all embryos can be frozen. In subsequent cycle, the lining is prepared with estrogen as long as needed till adequate thickness and pattern is achieved. Progesterone is then started and embryos are thawed in the appropriate time and transferred into the uterus.

6. Sildenafil (viagra) can be given as vaginal tablets but its value is questionable.

7. Gestational carriers can be used if all other methods fail.

Meticulous attention to the condition of the lining and cavity of the uterus is important during fertility treatment of the uterus. Endoscopic surgery and hormone preparation can improve the majority of the linings and increase the chance for embryo implantation

Idiopathic Infertility Treatment: what do you need to know

Idiopathic infertility (unexplained infertility) is defined as inability to conceive after trying for 6 months in women 35y or older and one year for women younger than 35, with no tubal, ovarian or male factor infertility. This diagnosis of idiopathic infertility is established after open fallopian tubes are detected in HSG or laparoscopy, regular ovulation is detected from history, lab tests and ultrasound and sperm is near normal on sperm analysis. These fertility tests can be performed within few days. Note that good health and physical fitness..etc are not factors here. Many women with terrible general health do conceive. On the other hand, many women in excellent physical fitness and sound health have extreme difficulty conceiving even with fertility treatment. Having difficulty getting pregnant without an apparent cause applies to a large category of the sub-fertile population and is puzzling to couples trying to conceive. The consensus of opinion among reproductive endocrinologist can divide the underlying factors for unexplained infertility into

1. Chromosomal abnormalities in the egg (low egg quality)

Abnormal eggs are present in every woman, albeit to a varying degree. Older women has more abnormal eggs. In addition, the fewer eggs you have the higher the proportion of abnormal eggs. There is no non-invasive test for egg quality and history, age, blood tests for ovarian reserve and antral follicle count detected on vaginal ultrasound are the most used methods.

Factors that point to low egg quality

Advanced maternal age,

Diminished ovarian reserve (e.g high FSH, low AMH), also prior surgery in the ovaries, smoking, family history of early menopause and exposure to chemotherapy

Abnormal chromosome configuration of male or female partner e.g chromosome translocation. Less than 5% of couples miscarry due to a translocation in the male or female partner.

2. Other factors: may be more prevalent in younger patient and include mild endometriosis, immunological factors as anti-sperm antibodies, abnormality in cervical mucus, abnormalities in the cavity of the uterus and endometrial lining. Generally, these are not considered major factors in idiopathic infertility. Mostly oral medication produce few or only one follicles, thus they do not increase te chance that one or more eggs are healthy leading to a pregnancy.

Treatment Options for Idiopathic Infertility

Oral medication – IUI or expectant treatment (intercourse)

Oral medications are either clomid (clomiphen citrate) or an aromatase inhibitor (mostly letrozole) are used. This is followed by intercourse or intrauterine insemination (IUI). The pregnancy rate is about 5% to 7% per treatment cycle. There is no evidence that oral medications followed by IUI are superior to just intercourse in treatment of unexplained infertility. The risk for multiple pregnancy is about 8%. However, because oral medication (clomid) widespread use, mostly without ultrasound monitoring, they are probably responsible for more multiple pregnancy than any other fertility treatment.

Injection medications – IUI

This treatment should probably be avoided in the majority of couples because of a. No added benefit: Pregnancy rate is not significantly higher than Clomid-IUI cycles; 9% pregnancy rate per treatment cycle and drops to 5% in women >38y. b. Risks: notably multiple pregnancy (two or more babies; 30%) and higher order multiple pregnancy (three or more babies; 3 to 8%). Multiple pregnancy has significant risks to the mother and babies. Preterm delivery can be associated with permanent neurological and intellectual defects in the babies. This risk can be minimized with careful stimulation under supervision of a reproductive endocrinologist, but cannot be completely prevented.

In Vitro Fertilization (IVF)

a. The pregnancy rate per an IVF treatment cycle is approximately 30% on average, three times that of IUI. The specific pregnancy rate is dependent on female age. The time to conception is also shorter than any other fertility treatment modality. The higher success rate can be further extended through the use of frozen embryos in couples that have good quality embryos available for freezing. The cumulative pregnancies resulting from fresh transfer and subsequent frozen-thaw embryo transfer can result in a very high odds for pregnancy. Frozen embryos can be used years after their creation, when ovarian reserve has considerably diminished. The contribution of IVF to treatment success becomes more pronounced in older women >38 years as the success of ovarian stimulation – IUI drops considerably. b. The risk for twins and higher order multiple pregnancy can be greatly minimized through single embryo transfer (1% twins and no higher order multiple pregnancy). In other words if you want to get pregnant faster, with one baby and at higher chance for success per treatment cycle strongly consider IVF with single embryo transfer.

Infertility Treatment Strategy for Idiopathic Infertility

Conventional fertility treatment: “expectant management → clomid / letrozole- IUI x2 to 3 cycles ‍→ gonadotropin – IUI x3 cycles → IVF ” is the old method of treatment for unexplained infertility Modern treatment of Unexplained infertility: ” expectant management or oral medication – IUI → IVF preferably with single embryo transfer “. Women 38 years and older modern treatment strategy suggests Immediate IVF as the initial fertility treatment. The modern paradigm for fertility treatment will lead to pregnancy faster, is more successful, minimize multiple pregnancy and is more cost effective (lower dollar cost per baby). The majority of women (>70%) with unexplained infertility especially women with normal ovarian reserve will succeed in delivering a baby.

Letrozole vs Clomid for Ovulation Induction in PCOS

Polycystic Ovary Syndrome (PCOS) is associated with two of the following criteria:

a. No ovulation (anovulation) or less frequent ovulation

b. Hign male hormone (androgen)

c. Polycystic appearance of the ovaries: large number of small follicles

Clomid is an oral medication that modulate or mask the estrogen receptor leading to release of internal FSH from the brain

Polycystic Ovary

Letrozole is an oral medicine that reduces estrogen production from the ovary through antagonizing the function of the aromatase enzyme, responsible for making estrogen. The brain respond by releasing FSH.

Which one is better?

In a recent good quality study, 750 infertile women, aged of 18-39 years, with a diagnosis of PCOS were studied. The women were randomly allocated to CC vs. letrozole for 5 treatment cycles. CC 50mg every day for 5 days (days 3-7 of cycle), or B) letrozole 2.5mg every day for 5 days (days 3-7 of cycle), for a total of 5 cycles or 25 weeks. The dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of CC a day (×5 days) or 7.5mg of letrozole a day (×5 days). 27.5% of women who received letrozole (Femara) had a live birth, compared with 19.5% of women treated with clomiphene. One quarter were clomid resistant and never ovulated.

Letrozole was associated with lower multiple pregnancy rates.

Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to clomiphene citrate.

Letrozole should be considered as a first line agent for induction of ovulation in women diagnosed with PCOS.

In general it is adviced that oral medication are tried first in PCOS before proceeding to injection medications (gonadotropins). Gonadotropins induce multiple ovulation and increase the risk for multiple pregnancy. If oral medications fail to induce ovulation or no pregnancy ensues, it is preferable to proceed to IVF with single embryo transfer and not injectable medications – IUI to avoid twins and higher order multiple pegnancy.

Asian Women & Fertility Problems

Majority of Asian Women and Men agree that it is very important for them to have children. Unfortunately, many Asian couples face challenge trying to conceive naturally or using fertility treatment. The decline in natural fertility and the lower success of IUI and IVF in Asian women is documented in The US, UK, China, Japan, Korea and other Asian countries.

Fertility in Asian countries has declined to the population replacement rate 2.1 or lower. Many factors contribute to decline in natural fertility in Asian women;

Ovarian Reserve in Asian Women

When compared to Caucasian women, Asian women undergoing IVF significantly produce less eggs at all Anti-Mullerian hormone (AMH) levels, even in women with high AMH. AMH is the most accurate marker for ovarian reserve.

Gynecologic and medical disorders that impairs fertility: PCOS, endometriosis and Systemic lupus (SLE) are more common in Asian women.

Vaginismus : may interfere with regular intercourse in some Asian women.

Culture : surveys of Asian women and men indicate that they are less likely to consent to be contacted for fertility research, are fatalistic about failure to conceive, less informed about fertility issues, only 36 percent knew that chances of getting pregnant declined with age, and are less likely to suspect a male factor.

Asian women are commonly late at seeking care for infertility and overestimate the chance for getting pregnant.

Genetics : Many genes are likely involved. FMR1 is a gene on X chromosome responsible for Fragile X syndrome and its variants. High repeats at this gene may reduce ovarian reserve.

Fertility Treatment Outcomes in Asian Couples

Pregnancy and delivery rates are lower in Asian women following ovarian stimulation and IUI compared to white women

IVF: when compared to white women in the US, 31 per cent of the Asian women gave birth successfully compared to 48 per cent of the white women. Asian women were also less likely to become pregnant; 43 percent against 59 per cent even after control for many fertility factors. Enodmetrial lining was thinner in Asian women compared to Caucasian women.

Asian women should be aware that fertility treatment may be less successful and seek care of a reproductive endocrinologist and fertility specialist as early as possible.

In addition there are other factors that require attention in Asian women during fertility treatment especially the higher prevalence of chronic hepatitis B infection.

After conception, asian women at are a higher risk for gestational diabetes.

What do Millennial women think about infertility?

Millennial generation were borne between 1982 and 2000. They have commonalities not shared by other generations. Generation Y is the highest-educated generation in American history.

On the Incidence of infertility in the US

The 2006–2010 National Survey of Family Growth (NSFG), indicates that the incidence of infertility among married women aged 15–44 is 6.0% (1.5 million) in 2006–2010, down from 8.5% in 1982 (2.4 Million women).
Impaired Fecundity (ability to have a live birth) among married women aged 15–44 Increased from 11% In 1982 To 15% In 2002, But decreased to 12% In 2006–2010. Both Infertility and impaired fecundity remain closely associated with age. The decline is probably reflects greater delay in childbearing (less women attempt to conceive thus less fit the definition of infertility).

Infertility prevalence can be estimated using two approaches: [1] a constructed measure derived from questions on sexual activity, contraception, relationship status, and pregnancy, and [2] a measure based on estimated time to pregnancy derived from the respondents’ current duration of pregnancy attempt (i.e., current duration approach). Prevalence was approximately twofold higher using the current duration approach (15.5%) vs. the constructed measure (7.0%). Both methods identified similar patterns of effect of increasing age (American Society for Reproductive Medicine 2013).

On Delaying Marriage in Generation Y

According to Pew Research Center analysis of U.S. Census data, 51% of US adults are currently married. Only 22% of Millennial women are married. The median age of first marriage for Gen Y women is 26.5 years and for men 28.7. Currently, there are more unmarried women in their early 30s than at any time in the last 60 years in the US.

Millennial Women : late marriage and late first birth

Millenials give birth to their first child many years later than predecessors. The mean age at first child’s birth for women was 23 and the mean age at first child’s birth for men was 25 and even much later in more recent research (The Guttmacher Institute). One-half of first births to women were in their 20s and two-thirds of first births were fathered by men who were in their 20s. On average, women aged 15-44 have 1.3 children as of the time of the interview.

Delay in bearing a child remains true even after cohabitation and other adult living arrangements are considered. The gap between first sex and first birth is 9+ years for Gen Y and 3+ years for Gen X.

Millennial Women Overestimate their Fertility Potential

Many Generation Y women, age 25 to 35, think a 30 year old woman has a 70-per cent chance of conceiving per month and in a 40 year old is close to 60% (Fertility IQ 2011 Survey, 1,000 women). Women were wrong most often about how long it takes to get pregnant and about how much fertility declines at various ages.
It is not clear why do millennials overestimate their fertility potenials possible explanations could be [1] Ignoring the disconnect between general health and ovarian aging; women can be very healthy and have very few eggs remaining in the ovary.
[2] Media celebrated older high profile and celebrity births in mid 40s.
[3] Some success of fertility treatment in older mothers.

Generation Y women are anxious about their fertility

Perceived infertility is the individual’s belief that she or he is unable to conceive or impregnate, regardless of whether this belief is medically accurate. Overall, 19% of women believed that they were very likely to be infertile, according to a Gutmacher institute 2012 survey of 1,800 unmarried men and women aged 18–29. A survey from Europe indicates that 31% of women and 52% of men believe that dramatic decline of fertility occurs after age 44.

On The Utilization of Fertility Services by Millennial Women

Millennial women appear to utilize Fertility Service different than generation X. Twelve percent of women aged 15-44 in 2006-2010 (7.3 million women), or their husbands or partners, had ever used infertility services. Among women aged 25-44, 17% (6.9 million) had ever used any infertility service, a significant decrease from 20% in 1995. Thirty-eight percent of nulliparous women with current fertility problems in 2006-2010 had ever used infertility services, significantly less than 56% of such women in 1982. In all survey years, ever-use of medical help to get pregnant was highest among older and nulliparous women (NSFG). Gen Y also overestimate the success rate of IVF.

Consideration of fertility by generation Y without changing reproductive plans include

No harm in evaluation of ovarian reserve. Some women, though very young, do have a diminished ovarian reserve to the extent that delay of seeking fertility treatment is detrimental to there ability to conceiving a biological child

Delaying childbearing does not mean ignoring fertility for an undefined period. Many options can be exercised to preserve fertility, including lifestyle modifications, egg freezing and embryo freezing.

Genetic screening : to assess the carrier state of the parents for common genetic diseases and the risk for transmission to children. Basic tests include common mutation for cystic fibrosis, spinal muscular atrophy and fragile X syndrome. Additional tests are related to ethnicity: hemoglobin abnormalities in blacks, Mediterraneans and Asians, Ashkenazi profile for European Jews, Tay Sach disease for Jews and French Canadians. Another approach is to apply a ‘universal genetic test’ that encompasses a large number of genetic mutations for many diseases irrespective of ethnicity to allow for detection of rarer genetic diseases or even to sequence the whole genes related to theses diseases.

Worried? have a risk factor? or wants a more proactive approach?: Obtain a sperm analysis, HSG to test if the tubes are open and ovarian reserve tests to investigate the function of the ovaries (vaginal ultrasound and blood work).

Intercourse: have regular intercourse three times a week without attempting to monitor or to time ovulation.

For How Long should you try to conceive before moving to the next step?

a. If a fertility factor known or detected e.g abnormal sperm analysis, blocked fallopian tube, no ovulation, low ovarian reserve, carrier of genetic mutation… you should seek consultation with a reproductive endocrinologist

b. If no fertility factor is known:

1. Female age < 35 years try to conceive for one year before seeking consultation with a reproductive endocrinologist

2. Female age ≥ 35 years seek consultation within 6 months if not pregnant

Dr. Amr Azim

Amr Azim, MD, FACOG is a reproductive endocrinologist and a fertility specialist with special training in treating simple and complex fertility problems. His areas of expertise are assisted reproduction and preservation of fertility